This invention comprises forming an intermediate product called 6,9 iminoether in a single step from erythromycin, which is transformed into a new and useful form of azithromycin, which is recovered by means of precipitation in hexane.
The antibiotic [2R-(2R*, 3S*, 4R*, 5R*, 8R*, 10R*, 11R*, 12S*, 13S*, 14R*)]-13-[(2,6-Dideoxy-3-C-methyl-3-O-methyl-xcex1-L-ribo-hexopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-heptamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-xcex2-D-xylo-hexopyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one, or IUPAC name 9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A, and generic name azithromycin is a broad-spectrum bactericide derived from erythromycin A. It differs structurally from erythromycin A due to the insertion of a methylated nitrogen moiety in position 9a in the lactone ring to create a 15-member macrolide. The structural modification significantly improves the antibiotic""s effectiveness against defective cell wall bacteria such as Mycoplasma pneumoniae, Chlamydia trachomatis, Chlamydia pneumoniae, etc. or the complex Mycobacteria avium, and achieves higher concentrations in the organism.
Azithromycin was discovered by Kobrehel et al. and first patented in Yugoslavia under number P592/81, and subsequently in Belgium under number 892357, under the name N-methyl-11-aza-10-deoxy-10-dihydroerythromycin A. The reaction sequence reported in the literature used to transform erythromycin A (1) into azithromycin (5) includes 4 principal steps, illustrated in FIG. 1, which are described in general terms below.
a) Formation of Oxime (2)
The oxime is formed from erythromycin A (1) by means of reaction with hydroxylamine hydrochloride in methanol.
b) Beckmann""s Rearrangement of the Oxime (2)
The intramolecular participation of the neighboring 6-hydroxy group is observed when Beckmann""s rearrangement is carried out at 0xc2x0 C. with p-toluenesulfonyl chloride in aqueous acetone, producing the 6,9-iminoether (3). This iminoether (3) and the process used to obtain it have been described in worldwide patent 26,758, and European patent 0,137,132. In U.S. Pat. No. 4,328,334, this iminoether is erroneously assigned to the structure of a lactam obtained using Beckmann""s rearrangement from the oxime of erythromycin A (1).
c) Reduction of the Iminoether (3)
Reduction of the iminoether (3) to the secondary amine (4) with sodium borohydride in methanol (J. Chem. Soc. Perkin Trans. 1, 1986, 1881; J. Org. Chem. 1997, 62, 7479-7481) or by catalytic hydrogenation in the presence of platinum dioxide and acetic acid as solvents (Tetrahedron Lett. 1994, 35, 3025).
d) Reductive Methylation of the Secondary Amine (4) to Obtain Azithromycin (5)
This process is described in U.S. Pat. No. 4,517,359, and in J. Chem. Res. 1988, 132. It consists basically of the Escheweiler-Clarke reaction and uses formaldehyde in acetic acid or formaldehyde, and formic acid in carbon tetrachloride or chloroform for methylation (FIG. 1). The main difficulty with these reactions, as they are described, is the formation of certain impurities such as formamide, derived from the amine 9-deoxy-9a-aza-9a-homoerythromycin A.
Recently, an alternative method was described in which the iminoether (3) can be reduced and the product obtained subsequently submitted to reductive methylation in the presence of formaldehyde with a noble metal as catalyst, without the need to isolate the intermediary (FIG. 1). Under these conditions, we obtain azithromycin with high purity and good yield in a single step from the iminoether (3) (European patent 0,879,823 A1).
Studies to elucidate the structure of azithromycin have brought to light two crystalline forms corresponding to the monohydrate and dihydrated forms (PCT/US87/01612, and J. Chem. Res. 1988, 132). Patent PCT/US87/01612 attributes to the azithromycin patented by Kobrehel et al. (Yugoslav patent P592/81, Belgian patent 892357 and U.S. Pat. No. 4,517,359) to correspond with the amorphous form.
This invention is intended to offer an alternative to known methods, in order to form the intermediary 6,9-iminoether in a single step from erythromycin to obtain 9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A, which is an evident improvement on existing preparation methods.
A further purpose of this invention is to prepare a novel form of 9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A with physical characteristics different from those detected thus far. B1